Pharmaceutical compositions for the treatment of skin

ABSTRACT

Pharmaceutical compositions for the treatment of skin have been prepared in a carrier which contains 40 to 60% of liquid paraffin, 40 to 60% of solid paraffin, and 0.5 to 5% of microcrystalline wax. The new carrier is especially suitable for readily oxidizable drugs such as dithranol and its derivatives. From the compositions of the invention it is possible to prepare sufficiently thin and hard, yet non-brittle sticks by means of which the drug can be applied at precisely the desired point of the skin.

This is a continuation of application Ser. No. 768,172, filed on Aug.22, 1985 and now abandoned, which is a continuation of application Ser.No. 478,529, filed Mar. 8, 1983, also now abandoned.

The present invention is concerned with new paraffin-basedpharmaceutical compositions to be applied to the skin. The invention isparticularly concerned with compositions containing readily oxidizabledrugs such as dithranol and its derivatives.

One of the drawbacks of the ointment bases used in the treatment of skindiseases is a tendency to spread from the affected skin to thesurrounding healthy skin and to clothes. This is particularlydetrimental when poorly penetrating ointments are used which containvaseline, paraffin oil, and soft waxes and which mainly affect the hornylayer and the epidermis. It is almost impossible to direct suchointments to the affected skin areas only, and dosage is difficult andextremely variable. This causes problems, especially if the ointmentincludes agents which irritate the skin or which colour the skin andclothes. One substance that affects the colours healthy skin isdithranol, or anthranil, still the most commonly used pharmaceutical forthe topical treatment of psoriasis.

P. G. Unna was the first scientist to develop ointment sticks containingdermatological agents in an attempt to reduce the above drawbacks/Monatschefte fur Praktische Dermatologi 1886:5 157-167/. According toUnna, dry, localised, spot-like skin diseases, such as psoriasis, dryeczemas, and spotty fungal skin diseases are best suited for treatmentwith ointment sticks. He suggests that the consistency of the ointmentstick be sufficiently soft so that little force is needed to apply astripe of ointment to the skin but, on the other hand, sufficiently hardso that the stick is not deformed when used or when exposed to hightemperatures. According to him, these requirements, though dependent onthe pharmaceutical used, could be satisfied by mixtures of olive oil andwax. Unna used colophonium as a hardening agent in addition to wax. Unnaused yellow beeswax (cera flava). Of the ointment stick formulaesuggested by Unna, almost all of which had stick bases of similarcompositions, the following two deserve mention: "Stilus acid. salicyl.unguens 10%" (Acid. salicyl. praec. 10.0, Colophoni 5.0, Cerae flavae45.0, Ol. oliv. prov. 40.0) and "Stilus Chrysarobini unguens 30%"(Chrysarobini 30.0, Colophoni 5.0, Cerae flavae 35.0, Ol. oliv. prov.30.0).

Unna also developed a paraffin ointment stick (Paraffini solid. 50.0,Paraffini liquid. 50.0), but, owing to the softness of the stick he didnot mix any pharmaceutical into the stick, but used the stick for oilingdry, horny skin in the way a lip pomada is used.

Since Unna's pioneering work, there have been very few papers onointment sticks in the treatment of skin diseases.

In 1941, F. Dietel mentioned the chrysarobin ointment stick for thetreatment of psoriasis /Deutsche medizinische Wochenschrift 1941:9237-9/. The composition of the stick was: Chrysarobin 30.0, Cerae flav.20.0, Adipis lanae 50.0.

In 1962 and 1966, there were two papers in which a close relative ofchrysarobin, cignolin (or dithranol) was used in ointment sticks/Weber,G., Medizinische Welt 1962:35 1839-40 and Schafe, M. K., Zeitschrift furHautund Geschlechtskrankheiten 1966 XL 347-51/. In both papers, the samecommercial preparation "Psoriacid" was used. The exact composition ofthe ointment base was not given, but it included Vaselinium album, Adepslanae, Paraff. solidum suffanita and Cera alba.

In 1970, F. Novotny used the following ointment stick base in his study:Oleum ricini 1.0, Paraffinum liquidum 4.0, Cera flava 43.0, Oleum cacao52.0, /Cs. Derm. 45 (1970):1 20-22/.

At present, only one ointment stick is available as a commercialpreparation in the Nordic countries. This is an "Anthraderm" stickcontaining 0.5, 1.0 or 2.0% dithranol (Pharma-medica). The compositionof the ointment base has not been given as a percentage, but the basecontains wool alcohols, cocoa oil, white beeswax, whale wax (cetaceum),and peanut oil (oleum arachidis) as well as 0.5% salicylic acid and0.02% butylated hydroxytoluene as stabilizers.

Even though stick-shaped preparations would be a good dosage form forseveral dermatological medicines in view of the treatment, they have notobtained a position of major importance in practice. This is because theointment stick bases so far developed have been too soft and havecontained oxidizable vegetable oils and animal fats. Rancid,peroxidating oils and fats, in turn, oxidize many pharmaceuticalsubstances such as dithranol and chrysarobin resulting in ineffectivecompounds. Unna stated in his monography discussing dithranol that, inthe presence of oxygen, the most important fatty acid in oliveoil--oleic acid--converts both chrysarobin and dithranol into dark,coloured compounds. It has also been noticed that the oxidation ofdithranol is faster, the more double bonds the fatty acid moleculecontains.

Some sticks also have the drawback that they contain wool grease, whichcan cause contact allergy.

These problems are associated with the "Anthraderm" stick. Theunsaturated fatty acids included in peanut oil and cocoa oil oxidizeafter the opening of the package and oxidize the dithranol into a dark,ineffective dimer. In spite of the antioxidants in the stick it must bestored in a cool place and used within 6 months of opening.

It has now been discovered that a paraffin ointment base which containsabout 40 to 60% of liquid paraffin (white vaseline), about 40 to 60% ofsolid paraffin, and about 0.5 to 5% of microcrystalline paraffin wax isa very good vehicle for stick-shaped dermatological preparations. Theessential aspect of the invention is the use of microwax as a hardeningagent. The stick cannot be hardened by increasing the proportion ofsolid paraffin, because the stick then tends to be brittle.

It has also been noticed that the carrier agent is particularly suitablefor readily oxidizable pharmaceuticals such as dithranol. In paraffinointments the storage stability of such agents is better than inointments containing unsaturated fats, because oxidation viaperoxidation is excluded. However, it is surprising that, when microwaxis added to a mixture of liquid and hard paraffin, ointment bases areobtained that given even better protection against oxidation.

The liquid paraffin used in pharmacy (Paraffinum subliquidum) is amixture of liquid hydrocarbons with a high boiling point (above 300°).It is commonly used for various ointments.

The solid paraffin (Paraffinum solidum) is a mixture of solidhydrocarbons mainly containing straight-chain alkales; the melting pointof the mixture is from 50° to 57°. It is used in various ointments as ahardening agent.

Microcrystalline waxes are mixtures of hydrocarbons whose melting pointis from 60° to 90° and which mainly contain cyclic hydrocarbons, somebranched acyclic alkanes, but very few n-alkanes. Their crystalstructure is considerably more delicate than that of paraffin waxes.They have been used as a coating agent for papers, textiles, metals andplastics. Microwaxes have also been used in wax coatings of cheese, inchewing gums and sweets, in cosmetic products such as lipsticks, skinointments and hair sprays, rubber glues, car, floor polishes, incrayons, and in candles.

In the ointment base presented here, microwaxes whose melting points arein the range 75° to 90°, in particular about 85°to 88°, will be used.

The composition of the ointment base varies depending on the materialsused, the desired hardness and toughness, and on the pharmaceutical tobe used and its concentration. A composition is recommended thatcontains about 45 to 55%, in particular about 48 to 51%, liquidparaffin, about 45 to 55%, in particular about 47 to 50%, solidparaffin, and about 1 to 3%, in particular about 1.5 to 2.5%, microwax.

If desired, stabilizers and other additives may be added.

From the mixture presented here, it is possible to prepare sufficientlythin and hard, yet non-brittle sticks which adhere well to the skin andby means of which the preparation can be applied at precisely thedesired point. The preparation is better than conventional ointmentbases, because the stick does not feel greasy. Moreover, thepharmaceutical remains on the desired area on the skin and does notspread to the healthy skin or adhere to clothes to the same extent asfrom conventional ointment bases. So far, dithranol has mainly been usedin hospital treatment. The sticks presented here also permit treatmentat home.

Readily oxidizable pharmaceuticals such as dithranol and chrysarobinkeep well in the ointment bases presented here.

Pharmaceuticals that can be used in the ointment bases presented hereinclude dithranol, 10-acyl derivatives of dithranol, chrysarobin,podophyllin, topical cytostats (e.g. 5-fluorouracil), idoxuridine,benzoylperoxine, and tretinoin.

In order to study storage stability, tests were performed on differentdithranol preparations. Dithranol is well known for its poor stability.Attempts have been made to stabilize dithranol preparations in variousways, e.g. by adding salicylic acid, but the resulting preparations havenot been pleasant to use.

In the stability tests, the stick presented here was compared with twoparaffin-based dithranol ointments as well as with the"Anthraderm"-stick.

In Table 1, a dithranol preparation in accordance with the invention iscompared with two paraffin-based preparations of the same concentration.The results indicate that in the ointment base presented here stabilityis better than in ointments containing vaseline or paraffin exclusively.

                  TABLE 1                                                         ______________________________________                                        Change in dithranol content during storage in an                              ointment base prepared according to the invention and in                      two ointment bases (3.0% preparation)                                         Storage                                                                              Ointment base                                                                              Ointment I  Ointment II                                   period as per inven-                                                                              (Vas. fl. 99.0%,                                                                          (Par. sol. 25.8%                              (months)                                                                             tion (Ex. 1) Par. sol. 1.0%)                                                                           Par. liq. 74.2%)                              ______________________________________                                        2      +1.9         -2.1        -3.4                                          5      +1.4         -1.7        -0.3                                          ______________________________________                                    

In Table 2, the new preparation was compared with the commercial"Anthraderm" preparation by determining the concentrations of quinoneand dimer formed in the preparations during storage. It can be seen thatthe storage stability of the preparation presented here is considerablybetter in spite of the fact that it does not contain any stabilizingagents.

                  TABLE 2                                                         ______________________________________                                        Quinone and dimer concentrations (%) in dithra-                               nol preparation according to the invention and in the                         commercial "Anthraderm" preparation during storage                                              Preparation as per                                          Temperature                                                                            Time     the invention                                                                              "Anthraderm"                                   °C.                                                                             (months) Quinone  Dimer Quinone                                                                              Dimer                                 ______________________________________                                        Room temp.                                                                             3        2 to 5   2 to 5                                                                              ca 10  10 to 20                              "        5        2 to 5   2 to 5                                                                              ca 10  10 to 20                              35°                                                                             2        2 to 5   2 to 5                                             "        5        2 to 5   2 to 5                                             ______________________________________                                    

The following examples will illustrate the invention.

EXAMPLE 1

    ______________________________________                                        Dithranol.           3.0                                                      Paraffin. liq.       48.0                                                     Paraffin. solid.     47.0                                                     Microwax (Acrowax 9240 G)                                                                          2.0                                                      ______________________________________                                    

The preparation is as follows: The base proper, the paraffins and themicrowax, are melted and mixed. The active agent is added to themixture, and the mixture is cast into appropriate moulds or intopackages which also function as casting moulds.

EXAMPLE 2

    ______________________________________                                        Chrysarobin.      15.0                                                        Paraff. liq.      42.0                                                        Paraff. sol.      40.0                                                        "Acrowax 9240 G"  3.0                                                         ______________________________________                                    

EXAMPLE 3

    ______________________________________                                        Podofyllin.       1.0                                                         Paraff. liq.      49.0                                                        Paraff. sol.      48.0                                                        "Acrowax 9240 G"  2.0                                                         ______________________________________                                    

EXAMPLE 4

    ______________________________________                                        Idoxuridine       3.0                                                         Paraff. liq.      48.0                                                        Paraff. sol.      47.0                                                        "Acrowax 9240 G"  2.0                                                         ______________________________________                                    

What is claimed is:
 1. A pharmaceutical composition consisting of atherapeutically effective amount of an otherwise readily oxidizable drugfor the treatment of skin contained in a carrier, said carrierconsisting of about 40 to 60% liquid paraffin, about 40 to 60% solidparaffin, and about 0.5 to 5% microcrystalline wax, said drug beingsubstantially stable against oxidation when contained in said carrier,said readily oxidizable drug being selected from the group consisting ofdithranol, 10-acyl dithranol, chrysarobin, podophyllin, 5-fluorouracil,idoxuridine, benzoylperoxine, and tretinoin.
 2. A composition accordingto claim 1 wherein the carrier consists of about 45 to 55% of liquidparaffin, about 45 to 55% of solid paraffin, and about 1 to 3% ofmicrocrystalline wax.
 3. A composition according to claim 2 wherein thecarrier consists of about 48 to 51% of liquid paraffin, about 47 to 50%of solid paraffin, and about 1.5 to 2.5% of microcrystalline wax.
 4. Acomposition according to claim 1 wherein said composition is in astick-shaped form.
 5. A composition according to claim 1 wherein themelting point of the microcrystalline wax is about 75° to 90° C.
 6. Acomposition according to claim 5 wherein the melting point of themicrocrystalline wax is about 85° to 88° C.
 7. A composition accordingto claim 2 wherein the melting point of the microcrystalline wax isabout 75° to 90° C.
 8. A composition according to claim 3 wherein themelting point of the microcrystalline wax is about 75° to 90° C.
 9. Acomposition according to claim 7 wherein the melting point of themicrocrystalline wax is about 85° to 88° C.
 10. A composition accordingto claim 8 wherein the melting point of the microcrystalline wax isabout 85° to 88° C.
 11. A composition according to claim 2 wherein thedrug is dithranol.
 12. A composition according to claim 2 wherein thedrug is 10-acyl dithranol.
 13. A composition according to claim 12wherein the carrier consists of about 49.5% of liquid paraffin, about48.5% of solid paraffin, and about 2.0% of microcrystalline wax whosemelting point is about 85° to 88° C.